Pruritus is an indication that is peculiar to skin, and is observed in a variety of dermatoses with inflammation. Pruritus may be provoked by some internal diseases (malignant tumors, diabetes mellitus, hepatic diseases, renal failure, hemodialysis, gout, thyroid diseases, hemopathy, and iron deficiency), pregnancy, and vermination. In some cases, drugs and psychogenic causes may also provoke pruritus.
Since pruritus is a subjective sensation, it is difficult to evaluate it quantitatively and objectively. The mechanism that induces pruritus has not yet been completely clarified.
Now, among the stimulants that are known to induce pruritus included are histamine, substance P, bradykinin, proteinases, prostaglandins, and opiate peptides. It is considered that pruritus is provoked by reaction of these pruritic stimulants to multistimuli-reacting nerve terminals existing at the border area between the epidermis and dermis (pruritic receptors), and by transfer of the resulting impulse to tractus spinothalamicus, thalamus, and cortex cerebri in that order ("The approach to the therapy for pruritus cutaneous", by Yoshiki Miyaji, p.22, 1996, Sentan Igakusya).
Pruritus is a symptom in which patients experience significant discomfort, and in severe cases may cause significant disturbance of normal life. In the therapy for pruritus, primarily the treatment of dermatitis or an underlying disease that induces pruritus is necessary, and particularly in cases of dermatoses, simultaneous therapy for pruritus itself is necessary, because scratching by a patient causes aggravation of symptoms.
Scratching is the most exacerbating factor of dermatitis, because scratching injures the skin resulting in defect of barrier function, and erosion by physical or chemical stimuli and bacterial infection may easily occur. Also, since the epidermis becomes thin and fragile and nerves are sensitized, pruritus readily occurs. As a result, a vicious cycle of repeated scratching begins.
For example, although the period of scratching resulting from pruritus during sleep is only 0.1% in healthy cases, the average period of scratching by patients with severe atopic dermatitis amounts to 24%. If an average period of sleep is assumed to be 8 hours, the period of scratching will reach about 2 hours. It is clear that the scratching during sleep exacerbates atopic dermatitis and becomes a factor in the occurrence of atpoic exanthema ("NIKKEI MEDICAL", Jul. 10, 1996, p13).
Thus the therapy for pruritus itself may be a radical treatment, particularly in cases of dermatosis with significant pruritus.
Examples of dermatoses generally subjected to therapy for such pruritus include atopic dermatitis, nervous dermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis, caterpillar dermatitis, asteatosis, senile pruritus cutaneuos, insect sting, photosensitive dermatosis, urticaria, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies, and acne vulgaris; and examples of visceral diseases complicated with pruritus and being particular problems include malignant tumors, diabetes mellitus, hepatic diseases, renal failure, hemodialysis, and pregnancy.
Examples of drugs generally used for therapy for such pruritus include oral drugs, e.g. topical, and antiallergic drugs; and topical preparations, e.g. antihistamines, adrenocortical steroid dermatologic preparations, nonsteroidal anti-inflammatory drugs, camphor, menthol, phenol, salicylic acid, tar, crotamiton, capsaicin, and humectants (urea, Hirudoid, and petrolatum). However, oral drugs have some problems, e.g. a long lag time before presenting effects, and adverse events such as suppressive effects on the central nervous system (drowsiness and fatigue) and impairment of the gastrointestinal system. Topical preparations also have some problems, e.g. insufficient antipruritic effect, while topical steroids particularly cause some problems of adverse events such as decreased adrenocortical function caused by protracted administration and the rebound phenomenon.
With regard to the relationship between opiates and pruritus, it has been clear that opiates have function not only as analgesics but also as chemical mediators of pruritus. It was first reported that endogenous opiate peptides such as .beta.-endorphin and enkephalin induced pruritus (B. Fjeller Acta, Dermato-Venereol., 61 (suppl. 97), 1-34, 1981). It has been shown that morphine or opiate compounds induced pruritus as an adverse event when administered epidurally or intrathecally (J. H. Jaffe and W. R. Martin, Goodman and Gilman's Pharmacological Basis of Theraputics, Macmillan, New York, 1985). On the other hand, it has been also shown that pruritus which induced by morphine administered intrathecally was suppressed by naloxone, a morphine antagonist (J. Bernstein et al., J. Invest. Dermatol., 78, 82-83, 1982), and severe pruritus induced by increasing concentration of endogenous opiate peptides in cases of cholestasia with hepathopathy was suppressed by nalmefene (J. R. Thornton and M. S. Losowsky, Br. Med. J., 297, 1501-1504, 1988). Generally, opiate agonists induce pruritus, whereas opiate antagonists are antipruritic. Recently, it has become evident that the serum concentration of .beta.-endorphin in children with atopic dermatitis is significantly higher than that of healthy children. And it was reported that opiate antagonists were effective in pruritus induced by atopic dermatitis (S. Georgala et al., J. Dermatol. Sci., 8, 125-128, 1994).
Thus, it has been generally recognized that opiate agonists induce pruritus and opiate antagonists have a possibility as antipruritic. However, opiate antagonists do not have a practical use as an antipruritic at the present stage.
An object of this invention is to provide an opiate .kappa. receptor agonist and an antipruritic comprising it that solves the above problems and which has a significantly prompt and potent antipruritic activity.